The altered metabolomics in ischemic stroke have been identified in older patients by several studies; however, until now only a few studies focused on young patients (7–10). The present study showed that serum metabolomic patterns were significantly different between young patients with ischemic stroke and healthy controls. The young ischemic stroke patients had increased L-methionine, homocysteine, glutamine, uric acid, GCDCA and PE (18:0/20:4, 16:0/22:5) levels, and decreased levels of L-citrulline, taurine, PC (16:2/22:6, 16:2/20:5, 15:0/18:2), and SM (d18:1/23:0, d20:0/19:1, d18:1/22:0, d16:0/26:1, d16:0/18:0, d16:0/22:1, d18:1/19:1, d16:0/17:1, d16:1/24:1, d18:1/19:0). Based on the identified metabolites, the metabolic pathways of arginine biosynthesis, glycerophospholipid metabolism, and taurine and hypotaurine metabolism were significantly enriched in the young patients with ischemic stroke.
Amino acids are an important group of metabolites that participate in multiple physiological and pathophysiological processes. Consistent with previous studies in older people, the present study showed that young patients with ischemic stroke had significantly increased L-methionine, homocysteine, uric acid, and glutamine levels [14–17]. As is known, both hyperhomocysteinemia and hyperuricemia are independent risk factors for stroke [14–15]. As an essential amino acid, methionine comes from dietary intake. Homocysteine is an intermediate in methionine metabolism, and a moderate methionine diet of four weeks can induce hyperhomocysteinemia [18]. The present study found that young patients with ischemic stroke had significantly increased L-methionine. The elevated methionine and homocysteine levels might be associated with increased methionine intake. L-glutamine has been considered a beneficial amino acid that has antioxidant and anti-inflammatory effects [19–20]. L-glutamine supplementation reduced infarct volume and promoted neurobehavioral recovery in stroke mice [20]. And brain injury increased glutamine output in the glutamate-glutamine cycle, and further protected neurons from damage [21]. Therefore, increased L-glutamine might be a compensatory reaction to brain injury. Unlike results in older people, our study found that young patients with ischemic stroke had decreased levels of L-citrulline and taurine. Nitric oxide (NO) is a gas-signal molecule with various physiological functions, including regulating the balance of blood flow and oxygen demand and neurovascular coupling in the brain [22–23]. Endogenous NO was mainly generated from the citrulline-arginine-NO pathway [24]. Previous studies have shown that L-citrulline supplementation increased the bioavailability of L-arginine and promoted NO synthesis [24]. Taurine is a semiessential amino acid in mammals and has been proven to have multiple beneficial effects, including attenuating inflammation- and endoplasmic reticulum stress–induced organ injuries [25–26]. Taurine treatment inhibited ethanol-mediated cell apoptosis in the cerebellum [27]. Therefore, decreased L-citrulline and taurine levels might be related to the pathogenesis of young patients with ischemic stroke.
As the key components of bile, bile acids are essential for regulating the digestion and absorption of dietary fat through the intestine. Recently, increasing evidence has shown that, beyond the gastrointestinal tract, circulating bile acids in the bloodstream also act as important signaling molecules for many pathophysiological processes [28–29]. The present study showed that the serum TBA levels were similar between the stroke and control groups, while the component of bile acid was significantly different. The present study showed that young patients with ischemic stroke had significantly increased GCDCA levels. GCDCA is a glycine-conjugated bile acid and has been demonstrated to be one of the most abundant bile acids in human serum [30–31]. GCDCA causes increased oxidative stress and promotes apoptosis by inducing JNK activation in rat hepatocytes [32]. Previous studies have shown that increased GCDCA levels are associated with liver injury induced by alcoholism or cholestasis [30–31]. Therefore, increased GCDCA levels might be related to the pathogenesis of young patients with ischemic stroke.
Several studies have demonstrated that lipid metabolites are associated with ischemic stroke [9, 33–34]. However, most previous studies were performed in older people, and their results also were controversial. The present study showed that lipid-related metabolites are significantly changed in young patients with ischemic stroke. PC, SM, and PE are all major constituents of cell membranes and play an important role in membrane-mediated cell signaling [35]. Previous studies have found that PC has many beneficial effects, including attenuating liver steatosis, slowing down aging-related processes, and improving brain function [36–37]. Consistent with previous research in older people, serum PCs were decreased in patients with ischemic stroke [33–34]. Moreover, the present study also found that young patients with ischemic stroke had increased PE (18:0/20:4, 16:0/22:5) levels and decreased levels of SM (d18:1/23:0, d20:0/19:1, d18:1/22:0, d16:0/26:1, d16:0/18:0, d16:0/22:1, d18:1/19:1, d16:0/17:1, d16:1/24:1, d18:1/19:0). SM and PE are abundant in brain, especially in the myelin sheet surrounding nerve cell axons [38–39]. Until now, the function of SM and PE remained unclear. Consistent with the present study, a recent study performed in three independent, follow-up, population-based cohorts also found a possible protective role for SM in stroke development [40]. The serum SM (32:1) level was demonstrated to inversely relate to the onset of ischemic stroke [40]. Further studies are needed to investigate whether changed levels of PC and PE are involved in the pathogenesis of young patients with ischemic stroke.
Besides the changed metabolites pattern, young patients with ischemic stroke had higher TG and FBG and lower HDL-C levels, when compared with age-, gender- and BMI-matched healthy controls. Consistent with the previous studies, relatively higher FBG within the normal range and increased TG and decreased HDL-C levels were observed in young patients with ischemic stroke but without a history of diabetes or hypercholesterolemia [9]. Therefore, more attention should be focused on young patients who have relatively higher FBG within the normal range and increased TG and decreased HDL-C levels.
The present study has some advantages and limitations. This was a case-control study, and the sample size was relatively small, which might limit the generalizability of the results. Our findings still warrant further studies to confirm our results. Ischemic stroke has an enormous influence on a working-age adult. Although several risk factors have been discovered, over a third of ischemic strokes in young adults remain cryptogenic. This study investigated metabolic differences and attempted to explore the possible mechanisms of ischemic stroke in young patients without common risk factors. Taken together, changes in metabolites might be involved in the pathogenesis of young patients with ischemic stroke. However, further independent validations, including human, animal, and cell experiments, are required before translating the results into clinical practice.